Monolithium acetylide is a valuable reagent for the preparation of ethynyl carbinols and terminal acetylenes. Monolithium acetylide has been used to ethynylate 17-keto steroids unsubstituted in the C.sub.16 position. However, it was previously necessary to utilize tetrahydrofuran (THF) or other etheral solvents to prepare the reagent. Such solvents cause problems in commercial scale processes.
It is well known to prepare 17-keto, 3-keto or 3, 17-diketo steroids with substituents on the A, B or C rings, see for example U.S. Pat. Nos. 3,166,551; 3,065,146; 3,516,991; 3,629,298 and 4,216,159.
M. M. Midland in J. Org. Chem. 40, 2250 (1975) reported reacting n-butylithium with acetylene in THF at low temperatures (&lt;-70.degree. ) and in dilute solutions to produce monolithium acetylide. (See also Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, Wiley, New York, 1967, p. 573). Midland found that warming or attempting to generate a more concentrated solution resulted in disproportionation to the insoluble dilithium acetylide and acetylene. This disproportionation is an important disadvantage and occurs in the absence of a complexing agent. (See Corbellini et al, Chem. Ind. (Milan) 42, 251 (1960) and Chem. Abstr. 54, 19250 (1960)).
To reduce or prevent the disproportionation, the monolithium acetylide is usually prepared in liquid ammonia, which presumably serves as an appropriate complexing agent. An amine such as ethylenediamine can also be used to stabilize monolithium acetylide. Ethylenediamine so greatly stabilizes monolithium acetylide that monolithium acetylide is sold commercially as a solid ethylenediamine complex. Ethylenediamine, while stabilizing monolithium acetylide to the point that it can be sold commercially, actually reduces the reactivity of the catalyst to the point that it is not useful for many ethynylation procedures.
U.S. Pat. No. 4,005,562 discloses the use of monolithium acetylide to ethynylate 17-keto steroids unsubstituted in the C.sub.16 position. The monolithium acetylide was prepared by bubbling acetylene into THF held at -70.degree. C. under anhydrous conditions followed by addition of butylithium. The 17-keto steroid was added to the unstabilized monolithium acetylide, and the mixture stirred for 3 hours at -70.degree. C. to produce the 17.alpha.-ethynyl-17.beta.-hydroxy steroid product.
U.S. Pat. No. 4,320,236 discloses the use of a monolithium acetylide-ammonium complex (which is well known to those skilled in the art) to ethynylate ketones at below about -30.degree. C. The examples in U.S. Pat. No. 4,320,236 disclose ethynylation reaction temperatures of -50.degree. to 10.degree. C. The unsaturated acyclic ketones ethynylated in U.S. Pat. No. 4,320,236 are very reactive whereas the monolithium acetylide reagent produced by the process of the present invention is reactive with steroidal 17-ketones which are highly substituted sterically hindered ketones such as cyclopentanones, that are ordinarily much less reactive.
U.S. Pat. No. 4,526,720 to Van Rheenen et al discloses a one pot and a two pot process for preparing monolithium acetylide. Each reaction involves contacting an organolithium compound with a solution containing acetylene in the presence of a stabilizing amine. The amine reacts with the organolithium compound to form a lithium complex and/or a corresponding lithium amide which is subsequently reacted with acetylene.
U.S. patent application Ser. No. 374,740, filed June 30, 1989, entitled, "Stable Lithium Amides and Reagent Compositions Thereof" of W. Novis Smith, which is herein incorporated by reference, discloses lithium amide reagent compositions with aromatic solvents which can be used in the process of the present invention.
The use of lithium acetylide in various forms is well known particularly for the formation of ethynyl alcohols from the reaction with ketones and aldehydes. In many of these cases, the lithium acetylide must be formed in solvents such as tetrahydrofuran, which are less desirable to use due to expense, or necessitate the use of extensive refrigeration (liquid ammonia), or require the use of a solid lithium acetylide/ethylene diamine complex or lithium amide. On a commercial scale, it is more desirable and more cost efficient to use liquid reagents or concentrated solutions of reagents which are stable. The use of storable solutions of lithium dialkylamides in aromatic solvents is the focus of this invention.